Systemic lupus erythematosis (SLE) is a complex autoimmune disease that affects multiple organ systems and affects preferentially young to middle-aged women. It has proven difficult to treat and the few effective therapies often have serious side effects. Recent research has identified a chronic elevation of interferon-a (IFN-a), produced primarily by a rare cell-type called the plasmacytoid dendritic cell, as an important factor in the pathogenesis of SLE. Raised serum levels of IFN-a have been observed in a proportion of SLE patients and correlate with both disease activity. Most patients have elevated expression of a characteristic group of IFN-a-inducible genes. We have developed a novel family of compounds that specifically inhibit the activation and production of IFN-a by plasmacytoid dendritic cells. The compounds, which we call immunoregulatory sequences (IRS), are short oligodeoxynucleotides with specific sequence motifs that inhibit signaling through Toll like receptors 7 and 9. These important innate immune receptors mediate signaling from the 2 major types of IFN-a inducers in SLE, viruses and immune complexes containing RNA or DNA. Thus, IRS are able to block the major stimuli for IFN-a in SLE without causing broad-based immunosuppression. The goal of this Phase I proposal is to complete the initial steps of preclinical development of our lead compound, IRS 954, as a therapeutic agent for the treatment of SLE. These include production and evaluation of modified forms with enhanced resistance to degradation (Aim 1), pharmacokinetic and pharmacodynamic evaluations of IRS 954 and stabilized modifications (Aim 2) and an initial evaluation of the normal mouse responses to the chronic treatment with the most stable form of the molecule. Successful completion of these aims will enable us to choose the appropriate entity to take forward into an IND-enabling clinical development program. (Brief description) Systemic lupus erythematosis is a serious autoimmune disease affecting over 1 million people in the U.S., primarily women. Current treatments for this disease have serious side effects, however recent discoveries suggest new methods of treatment that may be safer and more effective. We propose to develop a novel drug that specifically inhibits Interferon-alpha, a key factor in the disease. [unreadable] [unreadable] [unreadable]